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Immune Testing and Immune Treatment for IVF Failure and Recurrent Miscarriage

Consultation for IVF Treatment

Trying to conceive is an exciting time in one’s life, but it can also prove to be frustrating. Unfortunately, many couples struggle to become pregnant, and between numerous fertility tests, and finding the right doctor for you, the process may leave you feeling overwhelmed and unsure of where to turn.

Maybe you’ve been trying to become pregnant for years, or perhaps you’ve just been through your first failed IVF attempt. The truth of the matter is, many factors may be contributing to your infertility.

You may be curious about the possible reasons for unexplained IVF failure. A topic of increasing discussion is Immune Supportive Therapy — but what is this? Can you benefit from it?

We consulted Dr Amin Gorgy of The Fertility & Gynaecology Academy in London to shed some light on this topic. Dr Gorgy is one of the few leading fertility experts in the UK that regularly offer Immune Testing and Immune Treatments to qualifying patients.

Immune Supportive Therapy

The late Dr Alan E. Beer is widely credited to be a pioneer in the field of Reproductive Immunology.

Natural killer cells, which help to keep the body from developing cancer in an activated immune system, can over-populate the uterus or exist at too high levels within the blood stream. These cells then go overboard, killing the embryo or interfering with the endocrine system that produces the hormones that are essential for pregnancy. This response can often be associated with complications for both the mother and her baby if the pregnancy occurs without treatment to suppress the activity of the immune system.

Immune Supportive Therapy helps to restore this balance in the immune system.

Immune Supportive Therapy has been shown to improve live birth rate in patients with repeated IVF failure and reduce the risk of pregnancy loss in patients with recurrent miscarriage if they suffer from immune system imbalance. The treatment is tailored accordingly to the abnormal findings in the individual immune tests.

What should I do if I have had repeated IVF Implantation Failure or Recurrent Miscarriage?

The first thing you need to do is book a consultation. You do not necessarily need a referral letter to do this, however it is always a good idea to bring along your previous medical history, results of investigations and reports of procedures. Many of these may still be valid and will help to avoid repeated investigations.

During the consultation the different possible tests that might be necessary and how they may impact your chances of a successful pregnancy will be discussed.

Typically, it is found that patients suffer from a multifactorial problem. If you have one minor problem, you can likely overcome it naturally. However, two or more little problems can make a significantly bigger problem — which will then require medical help.

During the investigations, the following areas are explored for abnormalities:

  • Chromosomes (Karyotyping): to exclude monosomy, chromosomal abnormalities e.g. trisomy, translocations or missing parts of the chromosomes (deletions).
  • Uterine Cavity: to exclude polyps, adhesions or septum
  • Infection screening: to exclude deep or hidden genital infection
  • Sperm DNF Fragmantation: to exclude immaturity or breaking down of the DNA in the head of the sperm as this is the part that contributes to the embryos.
  • Immune System Imbalance: A comprehensive group of tests are carried out to check different aspects of the immune system and related clotting factors (thrombophilia).

Immune Testing and Immune Treatment

Immunological Research

Thrombophilia: Blood Clotting test
With this test, different aspects of blood clotting mechanisms are assessed including: full blood count, prothrombin time, APTT, fibrinogen, Antithrombin III, protein S, protein C, protein C resistance, Lupus Anticoagulant, Anticardiolipin Antibodies and gene mutation for factor II & V and MTHFR and sometimes PAI-1 4G/5G. Abnormal thrombophilia can cause miscarriage, implantation failure and other pregnancy complications through clotting in the placental vessels, inflammatory reaction at the lining of the womb (feto-maternal interface) and defective formation of new small blood vessels (angiogenesis) at the decidua (womb lining) and the placenta of early pregnancy.

Treatment with aspirin and heparin would help particularly in Antiphopholipid Antibody (sticky blood) Syndrome. Heparin helps to have a healthy decidua to receive the embryos and healthy placenta for a successful pregnancy. Adding IVIg to the formula has further improved the success rate in the presence of antibodies.

Antibodies
These tests include anti-nuclear antibodies, Double stranded DNA antibodies, histone antibodies, anti-thyroid antibodies and TSH. There is a strong correlation between the antibodies particularly anti-thyroid antibodies and miscarriage. Abnormal antibodies can result in reproductive failure, as they cause cell disruption and death together with an inflammatory reaction at the feto-maternal interface. The treatment includes steroids and possible IVIg to lower the level of such harmful antibodies. The latter is immune modulatory therapy that improves the immune tolerance of the mother to accept and keep the pregnancy.

Natural Killer (NK) Cell Assay
With this test, the woman’s blood for activity (cyto-toxicity) of her NK cells against placenta-like cells at different concentrations in the lab. IVIg and Intralipids are added in different concentrations to see which would help if needed. Additionally, the ratio of different sub-types of lymphocytes are checked that are relevant including NK cells to the total lymphocyte count. Then a management plan can be created based on the results.

Increased toxicity and ratio of NK cells make the environment in the uterus unfriendly and hostile for the embryos and pregnancy. NK cells in the uterus also produce inflammatory cytokines that will damage the uterine lining and the placenta. Increased ratio of some sub-types of lymphocytes is associated with antibodies against hormones and chemical transmitters which will affect your chance of achieving and maintaining pregnancy.

TH1/TH2 Intra-Cellular Cytokine Ratio
This is a ratio between two groups of chemicals in the body. The TH1 cytokines are defensive and include TNFα and IFNɤ. The TH2 cytokines including IL10 and others calm down the immune system and promote immune tolerance particularly during pregnancy so that the mother’s body will allow the embryos to implant and the pregnancy to be stable.

The defensive cytokines are important as well. They defend the body against bacteria, viruses and cancer changes. Normally during pregnancy, the ratio shifts towards TH2 to maintain the pregnancy. If the ratio is deviated significantly toward the defensive cytokines (TH1), the chances of conceiving become less and the risk of miscarriage becomes high. Th1 cytokine dominance will make the environment inside the uterus hostile to the embryos and the pregnancy. This damages the endometrium, and its receptivity. Additionally, it can also damage the embryos and make their chances of implantation much lower.

High TNFα can damage the eggs before they are released from the ovaries. It is imperative to bring the level down and keep it down for a couple of months before you try for pregnancy. The eggs that develop in the first two weeks of the cycle would have started to wake up from a long dormant phase over the previous two to three months, and it is important to wake up in a healthy environment to avoid the potential damage.

Increased ratio of TNFα is treated with TNFα antagonists e.g. humira in the form of two injections two weeks apart, and retest 7-10 days later. If the levels are not low enough, it is advised to have a further course of two injections. Usually it is supplemented with a second course and a drip of intralipids to boost the effect. Of course, not everyone will respond to TNFα antagonists adequately. However, the effect can be boosted with steroids and intralipids. Additionally, you might need IVIg early in pregnancy if you still have high TNFα.

Killer Immunoglobulin-like Receptors (KIRs)
These are receptors on the surface of NK cells which are in two groups; activating and inhibiting receptors. The absence of three specific activating receptors (2DS1, 2DS5 and 3DS1) is associated with miscarriage and probably increased risk of implantation failure. It should be noted that these patients often benefit from a drug called G-CSF (Neupogen). Originally, Neupogen was given to patients with low white cell count, as it stimulates the stem cells in the bone marrow to produce white cells. Observational studies reported that the drug reduced the risk of miscarriage in patients with history of recurrent miscarriage and missing these specific receptors. It was also found to improve the implantation ratio and increase the live birth rate in patients who are missing these receptors and have history of repeated IVF failure.

A group from New York found that G-CSF can help to increase the thickness of the lining of the womb in patients with such a problem. Neupogen can be given initially as a uterine wash around the time of ovulation, or the egg collection in IVF and as subcutaneous injections thereafter.

Leukocyte antibody detection (LAD) / Paternal Leukocyte Antibodies (PLA)
During pregnancy the placenta carries proteins that belong to the father which are foreign to the mother. The mother’s body will form antibodies against these antigens. These antibodies; often referred to as blocking antibodies, are useful as they do not reject the pregnancy but only cover the foreign proteins.The mother’s body then feels that the whole conception belongs to her and does not reject it with any other aggressive mechanism. There is evidence that the immune tolerance effect of the father’s antigens starts before pregnancy and shortly after intercourse.

The mother’s blood is tested against the father’s to check the level of these leukocyte antibodies, and If they are not high enough levels will need to be increased. This can be achieved by Lymphocyte Immune Therapy (LIT), where the partner’s lymphocytes are injected into the patient’s skin. The procedure is done twice, 3-4 weeks apart and retested 3-4 weeks later. If the good levels are not achieved one or two more booster doses can be administered. In addition to creating blocking antibodies, LIT induces immune tolerance in the mother’s body by stimulating specific immune tolerance cells called T-regulatory cells.

Husband & Wife IVF Treatment

DQα for both partners
DQα is name given to the genes that make up the protein in question on the surface of the lymphocytes and placenta. However, the problem might be more significant if the couple are sharing both genes. This might then also affect the efficacy of LIT therapy.

Blood T-Regulatory (T-reg) Cells
T-reg cells are a sub-type of T lymphocytes and are important for immune tolerance. Good levels are essential to prevent the body from producing antibodies against its own cells and tissues and hence reduce the risk of developing auto-immune disease. T-reg cells are very important for reproductive immune tolerance to allow the embryos to implant (increasing IVF success) so the pregnancy will continue (reducing the risk of miscarriage) in a healthy manner (reducing the risk of pre-eclampsia, intra-uterine growth restriction and other pregnancy complications).

Endometrial Biopsy for NK cells and Fox P3 +ve T-regulatory cells
The NK cells in the endometrium are the first to get in touch with the implanting embryo and the pregnancy. High levels of uterine NK cells will make the environment hostile for the embryos and the pregnancy. They are different from the peripheral blood NK cells as they are more likely to produce TH1 cytokines e.g. TNFα and IFNɤ than being cytotoxic. NK cells in the endometrium and placenta can increase by proliferation and by recruiting NK cells from the blood. Elevated levels of endometrial NK cells is treated with steroids and heparin which supports the development of the placenta. As uterine NK cells mainly produce inflammatory cytokines, it is very useful to take TNFα antagonist (Humira) the month before IVF or trying to conceive naturally.

Fox P3 +ve T-regulatory cells promote immune tolerance and their presence is very important for a successful pregnancy. If the level is low it can be promoted with various immune supportive therapy including steroids, IVIg, G-CSF (Neupogen) and LIT.

Why is Immune Therapy Controversial?

Immune Therapy should only be given to patients with immune system imbalance or autoimmune diseases:

Studies that were done using aspirin and heparin on all patients with unexplained recurrent miscarriage showed no significant improvement. However, when the same treatment was applied to patients with anti-phospholipid antibodies, there was a significant improvement in the “Live Birth” rate. The live birth rate increased further when IVIg was added as well. Adding IVIg also improved implantation ratio and hence success in IVF treatment which was not noticeable in this group of patients when they had aspirin and heparin only.

IVIg was given to all patients with unexplained recurrent miscarriage and understandably the effect was very much diluted so that the outcome showed no benefit. Ten studies of IVIg were reviewed together to establish a better guide to the doctors and the patients. Four of these studies reported significant enhancement of live birth rate with IVIg treatment, and six were unable to show significant benefit of the treatment. Among the trials showing benefit of treatment with IVIg, three out of four used immune test results to select patients for IVIg treatment. None of the six trials that were unable to benefit from IVIg therapy conducted immune testing for their patients.

Starting the treatment at the correct time is critical as well. It is very important to start immune therapy before pregnancy so that the environment is well prepared to receive the embryos for a successful and healthy pregnancy. In five of the above mentioned studies, the IVIg was started before pregnancy and 4 out of the 5 studies showed an improved live birth. None of the studies in which IVIg was given after pregnancy showed benefit. By the time pregnancy is confirmed, the damage might have already happened. In summary, in all three trials where IVIg was given to patients selected based on immune testing prior to pregnan, there was significant benefit and improved outcome of the pregnancy.

Lymphocyte Immune Therapy (LIT) was found to induce immune tolerance. Originally, this therapy was used to reduce organ rejection after kidney transplant. LIT anti-rejection effect could be through increasing Fox P3 T reg cells. In addition, it increases the blocking antibodies which protect the pregnancy against being rejected by the mother. In some cases where it is not suitable to use the partner’s blood (as in cases of infection or cancer), donor leukocytes have been used with similar success. Different studies produced conflicting results, very much related to the method used in the preparation. The study that stored the LIT preparations at 4⁰C overnight before being injected into the mothers did not improve the live birth, while the study that stored the sample at 37⁰ strikingly improved the live birth rate. It was found that the marker CD200⁺ on the lymphocytes that initiates the required immune tolerance response is significantly reduced by storing the separated lymphocytes overnight at 4⁰C prior to injecting them into the female partner. A study combining all the previous trials showed improvement in the live birth.

Combination immune therapy is probably the best possible approach. Combined therapy based on the test findings would improve different aspects of the immune system and potentiate drug effectiveness. Each therapy will target a particular problem, and at the same time would support other aspects of the immune system increasing the potential benefits of other therapies. Previous studies showed that adding IVIg to heparin therapy would increase the live birth rate from 19% to 55%. Furthermore, adding LIT on top of heparin and IVIg improved the live birth rate to 70%. Another study showed that adding TNFα antagonist to IVIg therapy inpatients with high NK cells and elevated TH1/TH2 intracellular cytokine ratio would significantly improved the live birth rate further.

Repeated IVF Implantation Failure and Recurrent Miscarriage can be due to multiple factors. However, with each problem discovered, there is a greater chance of future success. Immune Supportive Therapy has proved to improve live birth rate and reduce miscarriage rate in patients with an immune system imbalance. Exploring different systems to determine potential problems and taking the time to remedy them, can significantly maximise one’s chances of a successful pregnancy.

We thank Dr Gorgy from The Fertility and Gynaecology Academy, for providing specialist knowledge for this article.

The Fertility & Gynaecology Academy is an established Assisted Conception (IVF) unit in Central London that offers infertility treatments. It is also one of the few IVF clinics in the UK that offers personalised Immune Testing and Immune Treatment.

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